Gagete et al. World Allergy Organization Journal (2017):4 DOI 10.1186/s40413-017-0171-2
ORIGINAL RESEARCH
Open Access
Who has anaphylaxis in Brazil? Validation of a questionnaire for population studies Elaine Gagete1* , Lucilene Delazari dos Santos2, Leticia Gomes de Pontes2 and Fábio Morato Castro1
Abstract Background: The incidence of anaphylaxis is increasing in several parts of the world; thus, determining the prevalence of the disease in a given region is important to understand the factors involved and to promote measures to avoid this type of allergic reaction. Aiming this objective, we validated an instrument for a populationbasedstudy that assesses the prevalence of anaphylaxis in the Brazilian population. Methods: A questionnaire was generated in two variants - one for subjects seven years old or above (Group A) and another for children who were up to six years, 11 months and 29 days (Group B). The instrument was administered to patients with and without anaphylaxis. By allocating points, a score was calculated to differentiate subjects with and without the disease. After validation, the questionnaire was applied in the city of Botucatu (São Paulo state, Brazil), by randomly selecting houses and inviting residents to answer the questionnaire. Results: The questionnaire was reliable for identifying subjects with and without anaphylaxis in both groups, with a specificity and sensitivity above 90%. The prevalence of anaphylaxis in the pilot survey was 6.2% in Group A, however the evaluation was compromised in Group B by the low number of children below seven years of age due to random sampling of residences. Discussion: The prevalence of anaphylaxis in our pilot test (6.2%) was similar to major epidemiological surveys from several parts of the world, showing that anaphylaxis is not a rare disease. The instrument of the present work was suitable for this epidemiological survey and might be a good option for studying anaphylaxis in other populations. Conclusion: This instrument might be of particular value in places where researchers cannot access medical records to conduct similar epidemiological studies. Keywords: Anaphylaxis, Epidemiology, Surveys and questionnaires
Background Anaphylaxis is a severe, acute and potentially fatal systemic allergic reaction triggered by hypersensitivity mechanisms. The diagnosis of anaphylaxis is made based on the NIAID/FAAN (The National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network) 2005 consensus criteria [1]. A study of the accuracy of the NIAID/FAAN criteria for the diagnosis of anaphylaxis demonstrated that although their sensitivity is as high as 95%, their specificity is approximately 80% [2]. * Correspondence:
[email protected] 1 Faculdade de MedicinaUniversidade de São Paulo (Medical School of University of Sao Paulo (USP), Rua Tenente Silvio Bestetti 590, Botucatu, SP, Brazil Full list of author information is available at the end of the article
Because the incidence of anaphylaxis is reported to be increasing worldwide, studies on this disorder have become highly relevant. Three prior studies using data from the Rochester Epidemiology Project have studied the incidence of anaphylaxis among residents of Olmsted County, Minnesota, USA, over different time periods, which together span from 1983 to 2010 [3–5]. Their findings suggest that the incidence of anaphylaxis is increasing in that population, in both children and adults. Others have reported similar trends in the incidence of anaphylaxis overall and, more specifically, food-related anaphylaxis [6–8]. There are few epidemiological studies on anaphylaxis in Brazil [9, 10]. In this large country, the healthcare
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Gagete et al. World Allergy Organization Journal (2017):4
system is deficient in many aspects, and databases are not uniform and often not accessible. Because of the difficult access to patient records in emergency or outpatient units, questionnaires administered directly to the population are important instruments, provided they are validated and used properly. With the aim to build an adequate instrument to study the prevalence of anaphylaxis in the Brazilian population, we created and validated this questionnaire to be used in epidemiological surveys.
Methods This novel instrument was generated according to recommendations by Portney and Watkins, 2009 [11] and Reichenheim and Moraes, 2008 [12], and the process followed the bellow described stages: Comprehensive bibliographic review of scientific
material, published in Portuguese or English, to check whether other similar instruments had been developed and validated. Due to the lack of validated questionnaires with the desired characteristics, the next stage was pursued. Creating a questionnaire (Draft I) with questions in lay language, objective and grammatically correct sentences, using popular terms of everyday life. The questionnaire was conceived of as a mix between multiple-choice and short answer (open-ended) questions. Given the specific characteristics of the disease among small children compared to older children and adults, two variants of the questionnaire were generated: one for individuals who were seven years old or above (Group A) and another for children who were up to six years, 11 months and 29 days (Group B). Sending the questions of this Draft I to be analyzed by a body of ten judges, who were renowned professors in Allergology from several Medical Schools in Brazil. The following aspects were considered for each item: applicability, discriminative power, objectivity, biases, redundancy and classification capacity. The Likert scale was applied, with scores from 0 (“question entirely superfluous and inadequate”) to 5 (“question relevant and entirely adequate”). In addition to evaluating questions individually, the judges were also asked to grade the questionnaire as a whole from 0 to 5. Furthermore, each evaluator was encouraged to share their comments regarding the content and layout of the questionnaire. After the necessary corrections suggested by the judges, several trial tests were performed with small groups of patient until an updated version (Draft II) of the instrument was achieved.
Page 2 of 10
Draft II was then sent to ten other judges, who were
also professors from Medical Schools in Brazil specialists in Allergy and Immunology. This second panel of judges evaluated each question in a more directed manner, based on the following criteria: 0: superfluous and inadequate question; 1: reasonable question; and 2: relevant and adequate question. This new group of judges was also asked to grade the questionnaire as a whole on a scale of 0 to 5 (where 5 indicates an excellent instrument). Their comments were considered and edited into a final version of the questionnaire. This final version was administered to patients (or their legal guardians) with and without anaphylaxis. Those with anaphylaxis had been previously diagnosed by specialists who used the Sampon et al. [3] criteria, known to be a gold standard for anaphylaxis diagnosis. The other group of patients had also been previously diagnosed with other allergic but non-anaphylactic diseases, such as asthma, urticaria, rhinosinusitis and other nonanaphylactic forms of food and drug allergies. All these patients were recruited from specialized outpatient services at the Medical School of University of Sao Paulo (USP), the Medical School of São Paulo State University (UNESP- Botucatu), or private allergy clinics in Botucatu. The allergological work-up to determine the etiological data for each patient had been previously conducted by these outpatient services, which included a thorough interview and in vivo and/or in vitro diagnostic allergological methods. In anaphylactic patients, severity of reactions was classified according to the Mueller [13] (Group A) or Brown [14] (Group B) scales. This study has later correlated questionnaire results that indicated anaphylaxis with the clinical results from outpatient services that had previously determined who in fact had this disease. The purpose of this method was to look for a positive correlation between the results from the questionnaire and the known clinical diagnosis. All patients were informed of the objectives of the study and signed the informed consent form previously approved by the Ethics Committees of both the above universities. The only identifiers in the questionnaire were date of birth, ethnicity and name initials. The researchers did know the full identity of interviewees, and this was necessary to double-check the questionnaire’s score with the patient’s diagnosis. To validate the questionnaire, researchers had to know whether a patient who had a high score was in fact someone who had had an anaphylactic crisis. Instrument validation: the analysis of the questionnaires began with the allocation of weights
Gagete et al. World Allergy Organization Journal (2017):4
to the different questions to generate a score that divided the interviewees into groups with and without the disease based on a cut-off point that maximized sensitivity and specificity. The cut-off point was obtained by means of a receiver operating characteristic (ROC) curve. Weights were determined based on the relevance of symptoms for the diagnosis of anaphylaxis, and negative weights were assigned to exclude symptoms, evolution and treatments that are incompatible with the disease. All participants were asked to answer the same questionnaire approximately 60 days after their first response to assess the agreement rate of the answers. Pilot study: The questionnaire was administered in the population of Botucatu, which is a municipality in the Central West region of the state of São Paulo, with a population of 127,328 inhabitants, according to the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística – IBGE), census of 2010 [15]. Residences were selected according to a simple random sampling plan, and sample size was calculated based on 0.5% prevalence, 95% confidence and 0.05% sample error. Therefore, the sample size for Botucatu was at least 384 subjects. In each residence, individuals were invited to answer the questionnaire after signing the informed consent form. If they refused, a new residence was sampled until the total number of questionnaires was achieved. Participants (responding either for themselves or as legal
Fig. 1 Summary of Methodology
Page 3 of 10
guardians) were required to be above 16 years old in order to secure a high level of confidence in the answers provided. The interviewer was not to explain any question but could only read it to the interviewee, if he/she preferred to answer this way. If desired, the questionnaires were left in the home and collected a few days later. The final version of the questionnaires did not have any kind of personal identifier, so even in cases where the survey team came back to a house to pick up an envelope with a questionnaire, this information was not included when the results were compiled. A flow-chart with the summary of methodology is shown in Fig. 1.
Results Draft I of the questionnaire was composed of 22 questions with 111 sub-items. Of the ten judges who received this first questionnaire, eight returned it; however, one of them did not answer all questions and was therefore excluded. Nevertheless, his general comments were considered. Of the remaining seven judges, three graded the questionnaires as a whole with a score of 5, three of them with a score of 4, and one with a score of 3. None graded it with scores of 1 or 2. In the analysis of individual questions by each of the seven judges, a modal score of 3 or above was considered acceptable. According to this, 92% of the questions had acceptable clarity (that is, 92% of the questions
Gagete et al. World Allergy Organization Journal (2017):4
received a modal score of “3” or above from all seven judges). The other aspects were judged as follow: 72% received a grade of 3 or above for applicability, 80% for acceptable levels of biases, and 96% for acceptable levels of redundancy. Thus, there was little concern among authors regarding clarity, applicability, levels of biases and redundancy, given that all these criteria received good scores from the panel of judges. The criteria that received scores bellow acceptable levels were discriminatory power, objectivity and classification capacity. Namely, only 37% of the questions received a modal score of 3 or above for their discriminatory power, 41% for objectivity, and 47% for classification capacity. It is important to underscore that judges evaluated all questions according to the six criteria mentioned above (applicability, discriminative power, objectivity, levels of biases, redundancy, and classification capacity). This means that any one question could have received a high score in one criteria and a low score in another. For example, among all questions in the questionnaire, only 41% received an acceptable score regarding its objectivity, so the authors had to decide how to address the problem of lack of objectivity in 59% of them. It was not possible to simply eliminate the questions that scored low in objectivity because many of them had received good scores regarding their applicability, clarity and/or acceptable levels of biases. The authors then had to analyze individually each question, and decide whether to keep, modify, or eliminate it. Questions that had received a modal score of 3 or above in many criteria, and a low score in only a few, were either kept as they were or reworded. While questions that received scores below 3 in most criteria, were generally eliminated. This was a case by case process, discussed exhaustively amongst the authors. The reasoning behind this process was that it was important to create a questionnaire that overall had good levels of applicability, discriminative power, objectivity, classification capacity, and acceptable levels of biases and redundancy. Thus, if a question did not have a good score in one of these criteria, this would be compensated by other questions in the instrument having higher scores in the same criteria. After several tests with the above corrections, the instrument (now Draft II) was reduced to 10 questions with approximately 80 sub-items for each variant (Groups A and B). As mentioned earlier, a second panel of ten professors judged the questionnaire again. Two sub-items from variant A and one from variant B received a score of 0 or 1 by at least two judges and were removed from the questionnaire. All of the other items and sub-items received scores of 2 by at least nine of the ten judges. The final score of the questionnaire as a whole was 4 (two judges) or 5 (eight judges). Thus, a satisfying final version was achieved.
Page 4 of 10
A total of 199 patients were interviewed with this final version of these questionnaires and were classified as follows: Group A (117 patients): 59 anaphylactic individuals (29 female - fem); 58 control individuals (35 fem). Group B (82 patients): 26 anaphylactic children (11 fem); 56 control children (15 fem). Tables 1 and 2 (A and B for the respective variants) shows a summary of the questions and their respective weights. It is worth noting that when the interviewee did not answer most of the questions, we have discarded the questionnaire. It is important that all items of every question be answered to ensure reliable result, especially for scored questions. When few items were skipped (less than five), we considered the answer to be “no” or “do not remember”, which are equally weighted as zero. For complete questionnaire and raw dataset, please see online repository at https://figshare.com/s/5ae62c39e5d feb518b2e Note that: I. Question 1 divides the population between those who had at least one previous episode of an allergic crisis in their life and those who did not. Thus, this question is qualitative and does not enter the score. II. Starting with question 2, the interviewee or his/her legal guardian is asked to characterize the “worst allergic crisis he/she has ever had in his/her life”. The characterization of a single crisis (the worst) was necessary to avoid the summation of symptoms in the several eventually suffered crises, which we had noticed to be a trend among the interviewees during the trial testing phase of the instrument. The remaining questions (items related to triggers, outcome and treatment of the crisis) were formulated to remind the interviewee or the legal guardian to refer only to the worst suffered crisis. III. Questions 7, 9 and 10 also did not enter the score because they are descriptive. Specifically, these questions refer to the number of severe allergic reactions suffered by the interviewee; whether the triggers were confirmed by tests or exams; and how much time passed between the trigger and the onset of the crisis, respectively. IV. In question 8, each trigger is worth 1 point, in a non-additive manner, except for −2 points for house dust (mites) and −8 points for the emotional factor since we realized that these negative values were fundamental to distinguish between patients with asthma symptoms and those who overrated their symptoms, respectively. Aside from that, 7 points were added for patients who identified Hymenoptera insects as the trigger. This was necessary because some of the most severe cases of anaphylaxis,
Gagete et al. World Allergy Organization Journal (2017):4
Page 5 of 10
Table 1 Types of questions and respective weights in the questionnaire for patients in Group A
Table 1 Types of questions and respective weights in the questionnaire for patients in Group A (Continued)
Type of question
Question Weight
Type of question
Medical diagnosis suggestive of anaphylaxis
2.0
10
Symptoms
Question Weight
Medications
8.2
1
Insect (just Hymenoptera)
8.3
7
Rashes on the face and on the neck
3.1
1
Latex
8.4
1
Rashes on other parts of the body
3.2
1
Exercise
8.5
1
Itchy scalp
3.3
2
Surgical or medical procedure
8.6
1
Itching around the whole body
3.4
1
Dust
8.7
−3
Swollen eyes
3.5
3
Emotional
8.8
−5
Swollen lips
3.6
3
Other
8.9
1
Swollen tongue
3.7
3
Does not know/does not remember
8.10
0
Swollen genitals (private parts)
3.8
3
Other swollen body parts
3.9
3
Urticaria (hives)
3.10
3
Shortness of breath and/or cough and/or wheezing
3.11
1
Pallor
3.12
1
Cyanosis (purple extremities like nails, ear and lips) 3.13
4
Difficulties in speaking and/or changes in voice or crying
3.14
2
Difficulties in swallowing
3.15
4
Difficulties in thinking
3.16
2
Loss of consciousness or fainting
3.17
5
Cramps or stomach ache
3.18
1
Vomiting
3.19
3
Involuntary urination of fecal elimination
3.20
4
Other symptoms
3.21
1
3.22–1
5
Time from onset to full-blown crisis Less than 5 min Between 5 and 30 min
3.22–2
4
Between 30 min and 2 h
3.22–3
3
Between 2 and 8 h
3.22–4
2
Between 8 and 24 h
3.22–5
1
More than 24 h
3.22–6
-8
Does not know/does not remember
3.22–7
0
Treatment compatible with anaphylaxis
4 and 5
2
Treatment incompatible with anaphylaxis
4 and 5
−4
Less than 12 h
6.1
1
Between 12 and 24 h
6.2
1
Between 24 and 72 h
6.3
1
How much time passed until back to normal
Between 3 and 7 days
6.4
−2
More than 1 week
6.5
−5
Does not know/does not remember
6.6
0
8.1
1
Triggers Food
including blood pressure drop and collapse, were attributed to insects in a patient population that was otherwise oligosymptomatic. Of the 117 patients from Group A who answered the questionnaire for the first time, 36 returned the second questionnaire by mail (30.8%). The mean agreement rate of the answers was 88%. For Group B (82 patients), 23 returned the second questionnaire (28%), and the mean agreement rate was 87%. The results showed that mean scores were significantly higher in the anaphylaxis group compared to the control group (Table 3). The respective mean scores were: •Group A: 36.6 +/− 10.5 and 9.9 +/− 8.7 and. •Group B: 31.8 +/− 7.3 and 9.3 +/− 7.9 and. For anaphylaxis severity, the mild anaphylaxis groups (Grade I and II in Group A and “mild” in Group B) exhibited statistically significant differences with respect to those of severe anaphylaxis (Tables 4 and 5). There was no significant differentiation between moderate and severe anaphylaxis in either group. The analysis for patients with Grade I anaphylaxis was compromised due to the negligible number of participants. The ROC curve analysis (Fig. 2) indicated that the cutoff points for the diagnosis of anaphylaxis were 24.5 for Group A (90.0% sensitivity, 92.0% specificity) and 23.5 for Group B (21.5% sensitivity, 97.0% specificity). Considering that the NIAID/FAAN criteria [2] have a low specificity to diagnose anaphylaxis and that we sought to exclude from our study milder cases that could be misdiagnosed as other similar diseases, we randomly added 3 extra points to the cut-off value so that scores ≥28 and ≥25 were considered indicative of anaphylaxis in Groups A and B, respectively. Cronbach’s alpha coefficient was 0.68 for Group A and 0.35 for Group B. Once validated, the questionnaire was used in the city of Botucatu-SP, Brazil. A total of 407 questionnaires were completed, 387 by individuals from Group A (206
Gagete et al. World Allergy Organization Journal (2017):4
Page 6 of 10
Table 2 Types of questions and respective weights in the questionnaire for patients in Group B Type of question Medical diagnosis suggestive of anaphylaxis
Question 2.0
Table 3 Comparison between patients with and without anaphylaxis Weight 10
Age group Group A
Symptoms
Controls (n = 58) 9.9 ± 8.7
a
Anaphylaxis (n = 59) 36,6 ± 10,5
a
p < 0.001
9.0(−12.0–27.0)b
35.0 (19.0–64.0)b
Rashes all over the body
3.1
2
–
Controls (n = 56)
Anaphylaxis (n = 26)
–
Rashes on specific parts of body
3.2
2
Group B
9.3 ± 7.9a
31.8 ± 7.3a
< 0.001
Itching around the whole body
3.3
3
Swollen face
3.4
3
Swelling in other parts of the body
3.5
3
Urticaria (hives)
3.6
3
Shortness of breath and/or cough and/or wheezing
3.7
5
Voice or crying were husky or hoarse
3.8
5
Child was lethargic, did not react, was unresponsive
3.9
5
Diarrhea or softened stool
3.10
3
Vomiting
3.11
3
Less than 5 min
3.12–1
5
Between 5 and 30 min
3.12–2
4
Between 30 min and 2 h
3.12–3
3
Between 2 and 8 h
3.12–4
2
Between 8 and 24 h
3.12–5
1
Time from onset to full-blown crisis
More than 24 h
3.12–6
−8
Does not know/does not remember
3.12–7
0
Treatment compatible with anaphylaxis
4 and 5
2
Treatment incompatible with anaphylaxis
4 and 5
−4
Less than 12 h
6.1
1
Between 12 and 24 h
6.2
1
Between 24 and 72 h
6.3
1
Between 3 and 7 days
6.4
−2
More than 1 week
6.5
−5
Does not know/does not remember
6.6
0
How much time passed until back to normal
Triggers Food
8.1
1
Medications
8.2
1
Insect (just Hymenoptera)
8.3
7
Latex
8.4
1
9.0 (−8.0–27.0)
b
31.0 (14.0–48.0)
b
a
mean and standard deviation b median and maximum- minimum range
females) and 20 by individuals from Group B (8 females). Of the 387 respondents from Group A, 24 (6.2%) had a score of 28 or higher (suggestive of anaphylaxis). The reported causes for anaphylaxis were dipyrone (seven), shrimp or other crustaceans (five), insects (bees or wasps) (three), iodinated contrast (two) and unknown or unsure (seven). Group B, despite its small size, included four children with scores compatible with anaphylaxis (two to cow’s milk, one to bee venom and one unknown). With respect to the behavior of the anaphylactic patients from the studied population, the majority exhibited more than one episode (16 interviewees, 66.6%), and nine patients (37.5%) reported four or more episodes. Sixteen patients (66.66%) did not seek specialized evaluation and were only seen in the emergency room.
Discussion Anaphylaxis is a medical emergency and among the most severe diseases dealt with by allergists. In a nearly global manner and for reasons not fully understood, the incidence of anaphylaxis has increased [3–5], as has its severity [6–8]. This explains the growing interest in epidemiological surveys to map the problem in several populations. According to estimates, one out of 200 emergency care cases are caused by hypersensitivity reactions, ranging from mild urticaria to true anaphylactic reactions [16]. Epidemiological studies claim an estimated 50–2000 episodes of anaphylaxis per 100,000 persons, and, thus, approximately 2% of the population has already experienced at least one episode of anaphylaxis during their life [17].
Exercise
8.5
1
Surgical or medical procedure
8.6
1
Dust
8.7
−3
8.8
−5
Grade I (n = 2)
Grade II (n = 12)
Grade III (n = 29)
Grade IV (n = 16)
P
Emotional Other
8.9
1
28.28
24.7 ± 3.4
37.8 ± 7.8
44.5 ± 10.5